Relative Levels of α-, β-, and γ-mRNA from Patients with Severe and Intermediate β-Thalassemia Major

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Abstract
We have determined the relative quantities of γ- and β-mRNAs and the α/β-mRNA ratios in 37 patients with β-thalassemia major with specific genotypes, namely 8 with a homozygosity for codon (CD) 39 (C→T), 7 with a homozygosity for IVS-I-110 (G→A), 5 with a homozygosity for IVS-I-6 (T→C), for 15 patients with compound heterozygosities for 2 of these 3 mutations, and for 2 patients with the IVS-I-110 (G→A)/-8 7 (C→G) mutations. None had an α-thalassemia. Twelve patients had thalassemia intermedia and the remainder, transfusion-dependent severe conditions. Differences in phenotype were observed for compound heterozygotes involving the IVS-I-6 (T→C) mutation in combination with either the IVS-I-110 (G→A) or the CD 39 (C→T) mutations: patients with thalassemia intermedia had a lower α/ β-mRNA ratio, about half of that of the patients with severe β-thalassemia major. This might suggest a higher β-mRNA synthesis in some patients than in others with the same genotype; mutations in promoter, enhancer, and/or locus control region sequences may be responsible for these differences. In vitro chain synthesis data were too incomplete to be helpful in this study. The RT-PCR procedure allowed the separation of abnormal (extended) mRNA from normal β-RNA in subjects carrying the IVS-I-110 (G→T) mutation. The relative quantities of this βTh-mRNA (% of βA+ βTh) were determined by scanning of the appropriate autoradiograms; they averaged 25% for homozygotes and about 4% for heterozygotes, indicating a considerable instability of the message.

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